Pharmaceutical compositions containing 5-phenyl-1,3-dioxoalkenyl compounds

ABSTRACT

This invention relates to pharmaceutical compositions containing a class of 5-phenyl-1,3-dioxoalkenyl compounds useful as inhibitors of leukotriene biosynthesis and thus useful in the treatment of conditions associated with leukotrienes. This invention also relates to the use of the 5-phenyl-1,3-dioxoalkenyl compounds in the inhibition of leukotriene biosynthesis and thus in the treatment of conditions associated with leukotrienes. This invention further relates to a novel process for the preparation of the 5-phenyl-1,3-dioxoalkenyl compounds.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to pharmaceutical compositions containing a classof 5-phenyl-1,3-dioxoalkenyl compounds useful as inhibitors ofleukotriene biosynthesis. This invention also relates to the use of5-phenyl-1,3-dioxoalkenyl compounds as inhibitors of leukotrienebiosynthesis. By inhibiting leukotriene biosynthesis, the5-phenyl-1,3-dioxoalkenyl compounds of this invention are useful inpreventing or alleviating conditions associated with leukotrienes, suchas allergic reactions, inflammatory conditions, certain skin disorders,hyperalgetic conditions, and coronary vasoconstriction.

Arachidonic acid is converted enzymatically to various biologicallyactive products, such as prostaglandins, thromboxanes, varioushydroxyeicosatetraenoic and hydroperoxyeicosatetraenoic acids, andleukotrienes. The leukotrienes, products of the 5-lipoxygenase pathway,are implicated in allergic reactions, particularly asthma, see M.Griffin et al., N. Engl. J. Med., 308, 436-439 (1983); inflammatoryconditions; skin diseases such as psoriasis; hyperalgetic conditions,see J. D. Levine et al., J. Neuroscience 5, 3025-3029 (1985); andcoronary vasoconstriction. One leukotriene, LTD₄, is the major activeconstituent of slow reacting substance of anaphylaxis (SRS-A), a potentbronchoconstrictor that is released during allergic reactions. See R. A.Lewis and K. F. Austen, Nature, 293, 103-108 (1981). When administeredto humans and guinea pigs, LTD₄ causes bronchoconstriction by twomechanisms: (1) directly by stimulating smooth muscle; and (2)indirectly through release of thromboxane A2, which causes contractionof respiratory smooth muscle. Because antihistamines are ineffective inthe management of asthma, SRS-A is believed to be a mediator of thebronchoconstriction occurring during an allergic attack. LTD₄ may alsobe involved in other inflammatory conditions such as rheumatoidarthritis. Furthermore, LTD₄ is a potent coronary vasoconstrictor andinfluences contractile force in the myocardium and coronary flow rate ofthe isolated heart. See F. Michelassi et al., Science, 217, 841-843(1982); J. A. Burke et al., J. Pharmacol. and Exp. Therap . 221, 235-241(1982). Another leukotriene, LTC.sub. 4, is also a very potentbronchoconstrictor. A third leukotriene, LTB₄, is associated withleukocyte chemotaxis, a phenomenon in which leukocytes migrate from theblood to an inflammatory site in response to chemical or biologicalstimuli, and may be involved in both acute and chronic inflammation.LTB₄ also appears to be associated with rheumatoid spondylitis and gout.Thus, the 5-lipoxygenase inhibitors of this invention, by inhibiting theproduction of leukotrienes, may prevent or alleviate the allergic,inflammatory, and vasoconstrictive conditions associated withleukotrienes.

Non-steroidal antiinflammatory agents, such as aspirin, indomethacin,ibuprofen, and the like, inhibit prostaglandin biosynthesis by blockingthe cyclooxygenase pathway of arachidonic acid metabolism. As aconsequence, leukotriene levels may increase as arachidonic acid ismetabolized along the 5-lipoxygenase pathway, producing allergicreactions. Administration of 5-lipoxygenase inhibitors of this inventionmay be effective in reducing undesirable side effects associated withnon-steroidal antiinflammatory agents when administered separately or incombination.

See (1) P. Sirois, "Pharmacology of Leukotrienes" in Advances in LipidResearch, 21, 79-101 (1985); (2) M. K. Bach, "Inhibitors of LeukotrieneSynthesis and Action" in The Leukotrienes: Chemistry and Biology, L. W.Chakrin and D. M. Bailey, eds., pp. 163-194 (Orlando: Academic Press,1984); (3) M. K. Bach, Bioch. Pharmacol., 33, 515-521 (1984); (4) C. W.Lee et al., "Human Biology and Immunoreactivity of Leukotrienes" inAdvances in Inflammation Research, 6, 219-225 (1984); (5) P. Sharon andW. F. Stenson, Gastroenterology, 84, 454-460 (1984); (6) E. L. Becker,Trends Pharmacol. Sci., 4, 223-225 (1983); (7) Editorial, "Leukotrienesand Other Lipoxygenase Products in the Pathenogenesis and Therapy ofPsoriasis and Dermatoses" in Arch. Dermatol., 119, 541-547 (1983); (8)B. Samuelsson, Science, 220, 568-575 (1983); (9) R. A. Lewis et al.,Int. J. Immunopharmac., 4, 85-90 (1982); (10) M. W. Musch et al.,Science, 217, 1255-1256 (1982).

Unlike earlier therapeutic agents that treat symptoms rather thancauses, the compounds of this invention and the pharmaceuticalcompositions thereof block the formation of causative mediators ofallergic and inflammatory conditions and are therefore useful in thetreatment of allergic reactions, inflammation, and other conditionsassociated with leukotrienes.

This invention also relates to a process that permits the unexpectedlyefficient and convenient preparation of the 5-phenyl-1,3-dioxoalkenylcompounds of this invention. More specifically, this invention relatesto a process for preparing 5-phenyl-1,3-dioxoalkenyl compounds inimproved overall yield and purity by condensing optionally substitutedbenzaldehydes with acetoacetate esters, acetoacetamides, and2,4-alkanediones.

2. Prior Art

Condensation reactions of acetoacetate esters, acetoacetamides, or2,4-alkanediones of the general formula CH₃ (C═O)CH₂ (C═O)--R withbenzaldehydes normally occur at the active methylene (CH₂) group ratherthan at the methyl group. See, e.g., J. March, Advanced OrqanicChemistry, 2nd edition, pp. 854-859 (New-York: McGraw-Hill Book Company,1977). Condensation at the methyl group has been reported to occur onlyunder harsher conditions or by using more elaborate procedures thanemployed in the process of the present invention. For example, onemethod for preparing 5-phenyl-3-oxoalkenoates requires formation of aβ-keto ester dianion (by addition of two separate strong bases),followed by addition of an aldehyde and dehydration of the initiallyformed alcohol. S. N. Hucklin and L. Weiler, Tetrahedron Lett.,4835-4838 (1971). Another method for preparing 5-phenyl-3-oxoalkenoatesrequires forming an enol silyl ether from the corresponding β-keto esterdianion, followed by reaction with the aldehyde, generally in thepresence of an activating reagent such as titanium tetrachloride. T.-H.Chan and P. Brownbridge, J.C.S. Chem. Comm. 578-579 (1979); T.-H. Chanand P. Brownbridge, J.C.S. Chem. Comm., 20-21 (1981).

A condensation procedure employing titanium tetrachloride underconditions similar to those used in the present invention has beenpublished, but the product compounds disclosed, unlike those of thepresent invention, are formed by a condensation reaction at the activemethylene group and not by reaction at the methyl group. W. Lehnert,Synthesis, 667-669 (1974); W. Lehnert, Tetrahedron, 28, 663-666 (1972).

SUMMARY OF THE INVENTION

This invention relates to pharmaceutical compositions containing a classof 5-phenyl-1,3-dioxoalkenyl compounds of Formula I: ##STR1## togetherwith one or more non-toxic pharmaceutically acceptable carriers; whereinR¹ is:

(a) hydrogen;

(b) C₁ -C₁₀ alkyl;

(c) C₁ -C₆ alkoxy;

(d) NR⁵ R⁶ ; wherein R⁵ and R⁶, each being the same or different, are:

(i) hydrogen; or

(ii) C₁ -C₁₀ alkyl;

(e) phenyl or phenyl substituted with 1 to 3 substituents selected fromthe group consisting of:

(i) C₁ -C₁₀ alkyl;

(ii) C₁ -C₆ alkoxy;

(iii) nitro, with proviso that only one such substituent may be nitro;or

(iv) halogen;

(f) phenoxy or phenoxy substituted with 1 to 3 substituents selectedfrom the group consisting of:

(i) C₁ -C₁₀ alkyl;

(ii) C₁ -C₆ alkoxy;

(iii) nitro, with the proviso that only one such substituent may benitro; or

(iv) halogen;

(g) ##STR2## wherein R⁷, R⁸, and R⁹, each being the same or different,are:

(i) hydrogen;

(ii) C₁ -C₁₀ alkyl;

(iii) C₁ -C₆ alkoxy;

(iv) benzyl;

(v) phenoxy or phenoxy substituted with 1 to 3 substituents selectedfrom the group consisting of:

(A) C₁ -C₁₀ alkyl;

(B) C₁ -C₆ alkoxy; or

(C) halogen;

(vi) nitro, with the proviso that only one of R⁷, R⁸, and R⁹ may benitro;

(vii) halogen;

(viii) hydroxyl; or

(ix) R⁷ and R⁸ together are --CH═CH--CH═CH--;

wherein R², R³, and R⁴, each being the same or different, are:

(a) hydrogen;

(b) C₁ -C₁₀ alkyl;

(c) C₁ -C₆ alkoxy;

(d) benzyl;

(e) phenoxy or phenoxy substituted with 1 to 3 substituents selectedfrom the group consisting of:

(i) C₁ -C₁₀ alkyl;

(ii) C₁ -C₆ alkoxy; or

(iii) halogen;

(f) nitro, with the proviso that only one of R₂, R³, and R⁴ may benitro;

(g) halogen;

(h) hydroxyl; or

(i) R² and R³ together are --CH═CH--CH═CH--.

The term "C₁ -C₁₀ alkyl" refers to straight or branched chain alkylgroups having from 1 to 10 carbon atoms, also referred to as loweralkyl. Examples of C₁ -C₁₀ alkyl are methyl, ethyl, propyl, butyl,pentyl, hexyl, heptyl, octyl, nonyl, decyl, and the isomeric formsthereof.

The term "C₁ -C₆ alkoxy" refers to straight or branched chain alkoxygroups having from 1 to 6 carbon atoms. Examples of C₁ -C₆ alkoxy aremethoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, and the isomericforms thereof.

Examples of halogen are fluorine, chlorine, bromine, and iodine.

Although the structure shown for Formula I indicates one tautomericform, it is understood that this representation is for convenience onlyand that the scope of this invention includes as equivalents alltautomeric keto and enol forms of the compounds of this invention.

This invention also relates to the use of a class of5-phenyl-1,3-dioxoalkenyl compounds of Formula I in the treatment ofconditions associated with leukotrienes.

This invention further relates to a process for preparing the5-phenyl-1,3-dioxoalkenyl compounds of Formula I more efficiently andconveniently than is possible by other known methods. More specifically,the process of this invention involves the preparation of compounds ofFormula I by condensing optionally substituted benzaldehydes withacetoacetate esters, acetoacetamides, or 2,4-alkanediones in thepresence of a transition metal Lewis acid, preferably titaniumtetrachloride, and an organic amine.

DESCRIPTION OF THE INVENTION

The 5-phenyl-1,3-dioxoalkenyl compounds of this invention, Formula I,are prepared by condensing, in the presence of a transition metal Lewisacid and of an organic amine, optionally substituted benzaldehydes ofFormula II ##STR3## wherein R², R³, and R⁴ are above defined; withacetoacetate esters, acetoacetamides, or 2,4-alkanediones of Formula III##STR4## wherein R¹ is: (a) hydrogen;

(b) C₁ -C₁₀ alkyl;

(c) C₁ -C₆ alkoxy;

(d) NR⁵ R⁶ ; wherein R⁵ and R⁶, each being the same or different, are:

(i) hydrogen; or

(ii) C₁ -C₁₀ alkyl;

(e) phenyl or phenyl substituted with 1 to 3 substituents selected fromthe group consisting of:

(i) C₁ -C₁₀ alkyl;

(ii) C₁ -C₆ alkoxy;

(iii) nitro, With the proviso that only one such substituent may benitro; or

(iv) halogen;

(f) phenoxy or phenoxy substituted with 1 to 3 substituents selectedfrom the group consisting of:

(i) C₁ -C₁₀ alkyl;

(ii) C₁ -C₆ alkoxy;

(iii) nitro, with the proviso that only one such substituent may benitro; or

(iv) halogen.

Under the reaction conditions employed in the process of this invention,condensation occurs at the CH₃ CO-- methyl group of compounds of FormulaIII to form compounds of this invention rather than at the --CO--CH₂--CO-- methylene group of compounds of Formula III. The process of thisinvention possesses several advantages with respect to prior artmethods. In particular, the process of this invention does not requiregenerating or isolating special intermediate species such as thosecharacterizing the prior art methods described above. For example, thepresent process does not require forming a discrete dianionintermediate, thus avoiding the need for strong base. Furthermore, thepresent process does not employ a silylated or other such intermediate,thus avoiding complexities necessitated by an initial silylation, aseparate condensation step, and a dehydration step.

Preferably, a compound of Formula III and an equimolar quantity of acompound of Formula II are stirred together in a suitable organicsolvent in the presence of at least a two-fold molar quantity of asuitable organic amine and at least a slight excess (and preferably a1.3-fold to two-fold molar quantity) of a suitable transition metalLewis acid.

The term "transition metal Lewis acid" refers to chemical compoundscomprised of a central transition metal atom and appropriate ligands,such that the central metal atom can form chemical complexes byinteraction with electron-rich atoms of other compounds. Preferredtransition metals include titanium and zirconium. The term "ligand"refers to an electronegative atom or molecule that can chemically bindto a transition metal atom. Appropriate ligands for the process of thisinvention include halides, preferably chloride; organic amines; and thelike. Suitable transition metal Lewis acids for the process of thisinvention are transition metal Lewis acids that interact with a compoundof Formula III in such a way as to promote condensation at the CH₃ CO--methyl group. Examples of suitable transition metal Lewis acids aretitanium tetrahalides and zirconium tetrahalides. A preferred transitionmetal Lewis acid is titanium tetrachloride. For synthetic methods usingtitanium tetrachloride, see (1) B. Weidmann and D. Seebach, Angew Chem.Int. Ed. Engl., 22, 31-45 (1983); (2) M. T. Reetz, "OrganotitaniumReagents in Organic Synthesis. A Simple Means to Adjust Reactivity andSelectivity of Carbanions" in Top. Curr. Chem , 106, 1-54 (1982); and(3) T. Mukaiyama, Angew. Chem. Int. Ed. Engl., 16, 817-826 (1977).

Suitable organic solvents are organic liquids in which reactants may bedissolved or suspended but which are otherwise chemically inert.Examples of suitable organic solvents include alkanes and cycloalkanes;ethers and cyclic ethers; aromatic hydrocarbons; halocarbons, such aschloroform, dichloromethane, ethylene dichloride; and the like.Preferred organic solvents include tetrahydrofuran and dichloromethane,preferably tetrahydrofuran.

Suitable organic amines are basic nitrogen-containing organic compoundsthat are sufficiently basic to prevent the reaction medium from becomingacidic but which do not themselves form significant quantities ofbyproducts by chemical reaction with other reagents. Suitable organicamines include tertiary amines and hindered secondary amines. Suitabletertiary amines include trialkylamines, such as triethylamine andtributylamine; N-substituted heterocyclic compounds, such asN-methylmorpholine, N-methylpiperidine, and N,N'-dimethylpiperazine;polybasic tertiary amines, such as N,N,N',N'-tetramethylethylenediamineand N,N,N',N'-tetramethylpropylenediamine; and other tertiary aminesknown in the art. As used herein, the term "hindered secondary amine"refers to a secondary amine bearing sterically bulky substituents.Suitable hindered secondary amines include 2,2,6,6-tetramethylpiperidineand other hindered secondary amines known in the art. Preferred organicamines are tertiary amines, preferably triethylamine,N-methylmorpholine, and N,N,N',N'-tetramethylethylenediamine.

Although titanium tetrachloride is typically added as a solution incarbon tetrachloride, an alternative embodiment employs a preformedcomplex of N,N,N',N'-tetramethylethylenediamine and titaniumtetrachloride, which may be used where titanium tetrachloride isrequired and which may be used with or without adding excessN,N,N',N'-tetramethylethylenediamine or other suitable organic amine.The preparation of complexes of titanium tetrachloride and diamines arewell known in the art, for example, R. Tabacchi, L. Vuitel, and A.Jacot-Guillarmod, Helv. Chim. Acta. 53, 1495-1499 (1970).

The order of addition of the individual reagents to the reaction vesselis generally not critical, although the particular order of addition mayin some cases alter the yield or purity of compounds of this invention.The preferred order of addition for any particular reaction may dependupon the specific reagents used and the product desired. In a typicalreaction sequence, titanium tetrachloride (or other similar transitionmetal Lewis acid) in carbon tetrachloride is first added to the organicsolvent, preferably tetrahydrofuran or dichloromethane; normally, anequimolar to four-fold molar quantity of titanium tetrachloride relativeto the quantity of the compound of Formula III is used. Although thisaddition and the subsequent reaction steps may be performed over atemperature range of about 75° C. down to about -60° C., the titaniumtetrachloride is generally added to the solvent at temperatures betweenabout 0° C. and -50° C. An acetoacetate ester, acetoacetamide, or2,4-alkanedione of Formula III is added, preferably while thetemperature of the titanium tetrachloride mixture is maintained between0° and 40° C. The organic amine, typically in a two-fold to eight-foldmolar quantity relative to the compound of Formula III, is next added.Finally, an equimolar quantity (relative to the compound of Formula III)of an optionally substituted benzaldehyde of Formula II is added and thereaction allowed to proceed to completion. Compounds of this inventionmay be isolated by methods known to those skilled in the art. Apreferred isolation procedure involves adding water to the reactionmixture and performing solvent-solvent extraction, followed bychromatography. Condensation at the CH₃ CO-- methyl group rather than atthe --CO--CH₂ --CO-- methylene group is readily determined by oneskilled in the art using modern analytical methods. A preferredanalytical method is nuclear magnetic spectroscopy (nmr), by whichdisappearance of the nmr signal attributable to the methyl group (butnot the methylene group) indicates condensation only at the methylgroup.

Symmetrical bis(phenylalkene)diones of this invention, Formula IV##STR5## wherein R², R³, R⁴, R⁷, R⁸, and R⁹ are defined the same asabove for compounds of Formula I, may be formed by the reaction of anexcess of an optionally substituted benzaldehyde of Formula II with2,4-pentanedione (i.e., Formula III wherein R¹ is methyl) underconditions similar to those described above.

The compounds of this invention exhibited in vitro inhibition ofleukotriene biosynthesis. The leukotriene inhibitory activity of thecompounds of this invention illustrated in the examples was tested bythe following method.

Inhibition of Leukotriene Biosynthesis

Leukotriene C₄ (LTC₄) and leukotriene D₄ (LTD₄) biosynthesis by culturedrat basophilic leukemia cells (RBL-1 cells) was induced by incubation ofthe cells with an ionophore. See B. A. Jakschik, S. Falkenheim, and C.W. Parker, "Precursor Role of Arachidonic Acid in Release of SlowReacting Substance from Rat Basophilic Leukemia Cells," Proc Natl. Acad.Sci. U.S.A., 74, 4577-4581 (1977). The LTC₄ and LTD₄ biosynthesis wasquantitated at LTC₄ equivalents by radioimmunoassay using theLeukotriene C₄ [³ H]-RIA Kit available commercially from New EnglandNuclear, 549 Albany Street, Boston, Mass. Compounds were screenedinitially at 10⁻⁴ M or 10⁻⁵ M and compared with nordihydroguaiareticacid (the reference standard). A compound inhibiting leukotrienesynthesis at any given concentration by at least 30% relative to thereference standard was considered active. An IC₅₀ was determined foreach compound exhibiting at least 50% inhibition at the initialscreening dose. Table A lists IC₅₀ 's for representative compounds ofthis invention.

                  TABLE A                                                         ______________________________________                                        Inhibition of Leukotriene Biosynthesis                                        Compound      IC.sub.50 (μM)                                               ______________________________________                                        Example 1     20.0                                                            Example 20    27.0                                                            Example 21    26.5                                                            Example 23    67.0                                                            Example 27    27.2                                                            ______________________________________                                    

With respect to inhibition of leukotriene biosynthesis, the preferredembodiments of this invention include the use of compounds of thefollowing general structure, preferably as the pharmaceuticalcompositions thereof: ##STR6## wherein R¹ is C₁ -C₁₀ alkyl or C₁ -C₆alkoxy; and wherein R² is hydrogen and R³ is hydrogen, C₁ -C₁₀ alkyl, C₁-C₆ alkoxy, nitro, halogen, hydroxy, phenoxy, or p-chlorophenoxy, or R²and R³ together are --CH═CH--CH═CH--.

The most preferred embodiments of this invention include the use ofcompounds of the following general structure, preferably as thepharmaceutical compositions thereof: ##STR7## wherein R¹ is C₁ -C₆alkoxy; and wherein R² is hydrogen and R³ is hydrogen, C₁ -C₁₀ alkyl, C₁-C₆ alkoxy, halogen, phenoxy, or p-chlorophenoxy, or R² and R³ togetherare --CH═CH--CH═CH--.

By virtue of their activity as inhibitors of leukotriene biosynthesis,the compounds of Formula I are useful in treating conditions associatedwith leukotrienes, such as allergic reactions, particularly asthma;inflammatory conditions; and coronary vasoconstriction. A physician orveterinarian of ordinary skill can readily determine whether a subjectexhibits the condition. The preferred utility relates to treatment ofallergic reactions. Regardless of the route of administration selected,the compounds of the present invention are formulated intopharmaceutically acceptable dosage forms by conventional methods knownto those skilled in the art.

The compounds can be administered in such oral dosage forms as tablets,capsules, pills, powders, granules, elixirs, or syrups. The compoundsmay also be administered intravascularly, intraperitoneally,subcutaneously, intramuscularly, topically, or transdermally, usingforms known to the pharmaceutical art. In general, the preferred form ofadministration is oral. For the orally administered pharmaceuticalcompositions and methods of the present invention, the foregoing activeingredients will typically be administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as "carrier" materials) suitably selected with respect to theintended form of administration, that is, oral tablets, capsules,elixirs, syrups, and the like, and consistent with conventionalpharmaceutical practices. For instance, for oral administration in theform of tablets or capsules, the active drug components may be combinedwith any oral non-toxic pharmaceutically acceptable inert carrier suchas lactose, starch, sucrose, cellulose, magnesium stearate, dicalciumphosphate, calcium sulfate, mannitol, and the like, or variouscombinations thereof; for oral administration in liquid form, the activedrug components may be combined with any oral non-toxic pharmaceuticallyacceptable inert carrier such as water, saline, ethanol, polyethyleneglycol, propylene glycol, corn oil, cottonseed oil, peanut oil, sesameoil, benzyl alcohol, various buffers, and the like, or variouscombinations thereof. Moreover, when desired or necessary, suitablebinders, lubricants, disintegrating agents, and coloring agents can alsobe incorporated in the mixture. Suitable binders include starch,gelatin, natural sugars, corn sweeteners, natural and synthetic gumssuch as acacia, sodium alginate, carboxymethylcellulose, polyethyleneglycol, and waxes, or combinations thereof. Lubricants for use in thesedosage forms include boric acid, sodium benzoate, sodium acetate, sodiumchloride, and the like, or combinations thereof. Disintegrators include,without limitation, starch, methylcellulose, agar, bentonite, guar gum,and the like, or combinations thereof. Sweetening and flavoring agentsand preservatives can also be included where appropriate.

For intravascular, intraperitoneal, subcutaneous, or intramuscularadministration, active drug components may be combined with a suitablecarrier such as water, saline, aqueous dextrose, and the like.

By whatever route of administration selected, an effective but non-toxicquantity of the compound is employed in treatment. The dosage regimenfor preventing or treating leukotriene-associated conditions with thecompounds of this invention is selected in accordance with a variety offactors, including the type, age, weight, sex, and medical condition ofthe patient; the severity of the condition; the route of administration;and the particular compound employed. An ordinarily skilled physician orveterinarian can readily determine and prescribe the effective amount ofthe drug required to prevent or arrest the progress of the condition. Inso proceeding, the physician or veterinarian could employ relatively lowdoses at first and subsequently increase the dose until a maximumresponse is obtained. Dosages of the compounds of the invention areordinarily in the range of about 0.1 mg/kg per day up to about 100 mg/kgper day, preferably in the range of about 0.5 to 50 mg/kg per day.

The following examples further illustrate details for the preparation ofthe compounds of this invention. The invention, which is set forth inthe foregoing disclosure, is not to be construed or limited either inspirit or in scope by these examples. Those skilled in the art willreadily understand that known variations of the conditions and processesof the following preparative procedures can be used to prepare thesecompounds. All temperatures are degrees Celsius unless otherwise noted.

DESCRIPTION OF THE PREFERRED EMBODIMENTS EXAMPLE 1 ethyl3-oxo-5-phenyl-4-pentenoate, Procedure A ##STR8##

A solution of 6.6 ml (0.06 moles) of titanium tetrachloride in 30 ml ofcarbon tetrachloride was added dropwise with rapid stirring to 300 ml ofcold (-50° ) tetrahydrofuran. The mixture was allowed to warm to 0° anda solution of 5.85 g (0.045 moles) of ethyl acetoacetate in 50 ml oftetrahydrofuran was added dropwise over about 20 minutes. After themixture was stirred an additional 30 minutes, a solution of 25.2 ml(0.180 moles) of triethylamine in 50 ml of tetrahydrofuran was addeddropwise over 45 minutes. After the mixture was stirred an additional 45minutes, a solution of 4.8 g (0.045 moles) of benzaldehyde in 50 ml oftetrahydrofuran was added dropwise over 30 minutes. The reaction mixturewas allowed to warm to room temperature and then stirred for 24 hours.Water (50 ml) was added and the resultant two-phase mixture was stirredfor two hours. After the layers were separated, the aqueous layer wasextracted with 50 ml of ethyl acetate. The ethyl acetate extract wascombined with the initially separated organic layer, dried over sodiumsulfate, filtered, and concentrated in vacuo to 9.8 g of an oil.Chromatography on silica gel gave 7.4 g of the title compound as asolid, m.p. ca. 49°. Structure assignment was supported by nmr andinfrared spectra and by elemental analysis.

Analysis. Calcd. for C₁₃ H₁₄ O₃ : C, 71.54; H, 6.47. Found: C, 71.78; H,6.48.

The nmr spectrum (in CDCl₃) of the title compound exhibited no signalattributable to CH₃ CO-protons, but did exhibit signals attributable to--CO--CH₂ --CO-- methylene protons at δ1.44 ppm and to the correspondingenolate --C(OH)═CH--CO-- vinyl proton at δ5.25 ppm.

EXAMPLE 2 ethyl 3-oxo-2-(phenylmethylidene)butanoate ##STR9## A solutionof 5.0 g (0.047 moles) of benzaldehyde, 6.1 g (0.047 moles) of ethylacetoacetate, and 5 ml of triethylamine in 75 ml. of tetrahydrofuran wasstirred at room temperature for 144 hours in the absence of titaniumtetrachloride. The reaction mixture was concentrated in vacuo to drynessand the residue chromatographed on silica gel to give both E and Zisomers of the title compound. The products formed by this procedureexhibited nmr signals (in CDCl₃) attributable to CH₃ CO-- but did notexhibit signals characteristic of the title compound of Example 1 (i.e.,attributable to --CO--CH₂ --CO-- methylene protons or to the enolateisomer). Structure assignment of the major isomer was also supported byelemental analysis.

Major isomer:

m.p. ca. 58°.

nmr (CDCl₃): δ(ppm) 2.40 (s, CH₃ CO); 7.63 (s, --CH═).

Analysis. Calcd. for C₁₃ H₁₄ O₃ : C, 71.54; H, 6.47. Found: C, 71.52; H,6.28.

Minor isomer:

nmr (CDCl₃) δ(ppm) 2.27 (s, CH₃ CO); 7.55 (s, --CH═).

EXAMPLE 3 ethyl 3-oxo-5-phenyl-4-pentenoate, Procedure B

The title compound was prepared by the method of Example 1 except that,after the water was added, the mixture was heated at reflux for 20hours. The material prepared by this procedure was identical to thatprepared by the method of Example 1, as indicated by the reverse phasechromatography. The reverse phase chromatographic system employed a 4.6mm×25 cm column packed with an octadecyl-bonded silica gel (5 micronparticle size) stationary support. Samples containing the reactionproducts were eluted with a 45:55 (by volume) mixture of acetonitrileand water, and components were detected by ultraviolet absorption at 254nm.

EXAMPLE 4 ethyl 3-oxo-5-phenyl-4-pentenoate, Procedure C

The title compound was prepared by the method of Example 1 except thatthe titanium tetrachloride solution in carbon tetrachloride was added totetrahydrofuran at 0° rather than at -50°. The material prepared by thisprocedure was identical to that prepared by the method of Example 1, asindicated by the reverse phase chromatographic method described inExample 2.

EXAMPLE 5 ethyl 3-oxo-5-phenyl-4-pentenoate, Procedure D

The title compound was prepared by the method of Example 1 usingdichloromethane as solvent instead of tetrahydrofuran. The materialprepared by this procedure was identical to that prepared by the methodof Example 1, as indicated by the reverse phase chromatographic methoddescribed in Example 2.

EXAMPLE 6 ethyl 3-oxo-5-phenyl-4-pentenoate, Procedure E

The title compound was prepared by the method of Example 1 using2,2,6,6-tetramethylpiperidine as base instead of triethylamine. Thematerial prepared by this procedure was identical to that prepared bythe method of Example 1, as indicated by the reverse phasechromatographic method described in Example 2.

EXAMPLE 7 ethyl 3-oxo-5-phenyl-4-pentenoate, Procedure F

The title compound was prepared by the method of Example 1 usingN-methylmorpholine as base instead of triethylamine. The materialprepared by this procedure was identical to that prepared by the methodof Example 1, as indicated by the reverse phase chromatographic methoddescribed in Example 2.

EXAMPLE 8 ethyl 3-oxo-5-phenyl-4-pentenoate, Procedure G

The title compound was prepared by the method of Example 7 except that atwo-fold molar quantity of titanium tetrachloride relative to ethylacetoacetate was used. The material prepared by this procedure wasidentical to that prepared by the method of Example 1, as indicated bythe reverse phase chromatographic method described in Example 2.

EXAMPLE 9 ethyl 3-oxo-5-phenyl-4-pentenoate, Procedure H

The title compound was prepared by the method of Example 7 except that athree-fold molar quantity of titanium tetrachloride and a six-fold molarquantity of N-methylmorpholine relative to ethyl acetoacetate were used.The material prepared by this procedure was identical to that preparedby the method of Example 1, as indicated by the reverse phasechromatographic method described in Example 2.

EXAMPLE 10 ethyl 3-oxo-5-phenyl-4-pentenoate, Procedure I

The title compound was prepared by the method of Example 1 usingzirconium tetrachloride instead of titanium tetrachloride. The materialprepared by this procedure was identical to that prepared by the methodof Example 1, as indicated by the reverse phase chromatographic methoddescribed in Example 2.

EXAMPLE 11 ethyl 3-oxo-5-phenyl-4-pentenoate, Procedure J

A solution of 0.020 moles of titanium tetrachloride in 5 ml of carbontetrachloride was added dropwise at room temperature to 50 ml ofdichloromethane. The mixture was cooled to 0° and a solution of 0.020moles of N,N,N',N'-tetramethylethylenediamine in 5 ml of dichloromethanewas added dropwise over 15 minutes. After the mixture was stirred anadditional hour, a solution of 0.015 moles of ethyl acetoacetate in 10ml of dichloromethane was added dropwise over 15 minutes. After themixture was stirred an additional hour, a solution of 0.030 moles oftriethylamine in 15 ml of dichloromethane was added over 10 minutes.After thirty minutes, a solution of 0.015 moles of benzaldehyde in 10 mlof dichloromethane was added over 10 minutes. The reaction mixture wasstirred for 20 hours. Water (25 ml) was added and the resultanttwo-phase mixture was stirred for two hours. After the layers wereseparated, the aqueous layer was extracted with 50 ml of ethyl acetate.The ethyl acetate extract was combined with the initially separatedorganic layer, dried over sodium sulfate, filtered, and concentrated invacuo to an oil. Chromatography on silica gel gave the title compound asa solid. The material prepared by this procedure was identical to thatprepared by the method of Example 1, as indicated by the reverse phasechromatographic method described in Example 2.

EXAMPLE 12 ethyl 3-oxo-5-phenyl-4-pentenoate, Procedure K

The title compound was prepared by the method of Example 11 using excessN,N,N',N'-tetramethylethylenediamine and no added triethylamine. Thematerial prepared by this procedure was identical to that prepared bythe method of Example 1, as indicated by the reverse phasechromatographic method described in Example 2.

EXAMPLE 13 ethyl 3-oxo-5-phenyl-4-pentenoate, Procedure L

The title compound was prepared by the method of Example 1 except that atitanium tetrachloride/N,N,N',N'-tetramethylethylenediamine complex wasused instead of titanium tetrachloride alone. The complex was preparedfrom titanium tetrachloride and N,N,N',N'-tetramethylethylenediamine asdescribed in Example 11 and isolated by filtration.

EXAMPLE 14 ethyl 3-oxo-5-phenyl-4-pentenoate, Procedure M

The title compound was prepared by the method of Example 20 (below)using excess benzaldehyde instead of 3-phenoxybenzaldehyde. The materialprepared by this procedure was identical to that prepared by the methodof Example 1, as indicated by the reverse phase chromatographic methoddescribed in Example 2.

EXAMPLE 15 ethyl 3-oxo-5-phenyl-4-pentenoate, Procedure N

The title compound was prepared by the method of Example 14 except thatthe reaction was conducted at room temperature instead of 0°. Thematerial prepared by this procedure was identical to that prepared bythe method of Example 1, as indicated by the reverse phasechromatographic method described in Example 2.

EXAMPLE 16 ethyl 3-oxo-5-phenyl-4-pentenoate, Procedure O

A solution of 0.020 moles of titanium tetrachloride in 15 ml of carbontetrachloride was added to a cold (0°) solution of 0.015 moles of ethylacetoacetate in 75 ml of tetrahydrofuran. After the mixture was stirredfor 15 minutes, a solution of 0.060 mole of triethylamine in 15 ml oftetrahydrofuran was added dropwise over five minutes. After the mixturewas stirred an additional 15 minutes, a solution of 0.015 moles ofbenzaldehyde in 15 ml of tetrahydrofuran was added over 10 minutes. Thereaction mixture was then stirred for 20 hours, after which the titlecompound was isolated by the extraction and chromatography methodsdescribed in Example 1. The material prepared by this procedure wasidentical to that prepared by the method of Example 1, as indicated bythe reverse phase chromatographic method described in Example 2.

EXAMPLE 17 ethyl 3-oxo-5-phenyl-4-pentenoate, Procedure P

To a cold (5°) solution of 0.015 moles of benzaldehyde and 0.015 molesof ethyl acetoacetate in 60 ml of tetrahydrofuran was added 0.060 moleof triethylamine. After the mixture was stirred for 5 minutes, asolution of 0.020 moles of titanium tetrachloride in 15 ml of carbontetrachloride was added dropwise over 10 minutes. The reaction mixturewas then stirred for 20 hours, after which the title product wasisolated by the extraction and chromatography methods described inExample 1. The material prepared by this procedure was identical to thatprepared by the method of Example 1, as indicated by the reverse phasechromatographic method described in Example 2.

EXAMPLE 18 ethyl 3-oxo-5-phenyl-4-pentenoate, Procedure Q

A solution of 0.020 moles of titanium tetrachloride in 15 ml of carbontetrachloride was added over a period of 10 minutes to a cold (5°)solution of 0.015 moles of ethyl acetoacetate and 0.015 moles ofbenzaldehyde in 60 ml of tetrahydrofuran. After the mixture was stirredfor 1.5 hours, a solution of 0.060 mole of triethylamine in 15 ml oftetrahydrofuran was added dropwise. The reaction mixture was thenstirred for 20 hours, after which the title compound was isolated by theextraction and chromatography methods described in Example 1. Thematerial prepared by this procedure was identical to that prepared bythe method of Example 1, as indicated by the reverse phasechromatographic method described in Example 2.

EXAMPLE 19 ethyl 3-oxo-5-phenyl-4-pentenoate, Procedure R

The title compound was prepared by the method of Example 1 except thatthe ethyl acetoacetate addition and subsequent steps of the reactionwere conducted at 39°. The material prepared by this procedure wasidentical to that prepared by the method of Example 1, as indicated bythe reverse phase chromatographic method described in Example 2.

EXAMPLE 20 ethyl 3-oxo-5-(3-phenoxyphenyl)-4-pentenoate ##STR10##

A solution of 0.10 moles of titanium tetrachloride in 25 ml of carbontetrachloride was added with rapid stirring over 15 minutes to 200 ml ofcold (0°) tetrahydrofuran. After the mixture was stirred an additional15 minutes, a solution of 0.05 moles of 3-phenoxybenzaldehyde in 15 mlof tetrahydrofuran was added over 30 minutes. A solution of 0.05 molesof ethyl acetoacetate in 15 ml of tetrahydrofuran was then added. Asolution of 22 ml of N-methylmorpholine in 30 ml of tetrahydrofuran wasadded dropwise over three hours. The reaction mixture was then stirredfor 20 hours, after which time 50 ml of water and 50 ml of diethyl etherwere added. After the resultant layers were separated, the aqueous layerwas extracted with 50 ml of diethyl ether. The diethyl ether extract wascombined with the initially separated organic layer, dried over sodiumsulfate, filtered, and concentrated in vacuo to an oil. Chromatographyon silica gel gave the title compound as an oil. Structure assignmentwas supported by nmr and infrared spectra and by elemental analysis.

Analysis. Calcd. for C₁₉ H₁₈ O₄ : C, 73.53; H, 5.85. Found: C, 73.72; H,6.20.

EXAMPLE 21 ethyl 5-[3-(4-chlorophenoxy)phenyl]-3-oxo-4-pentenoate##STR11##

The title compound was prepared by the method of Example 20 using3-(4-chlorophenoxy)benzaldehyde instead of 3-phenoxybenzaldehyde.Structure assignment was supported by nmr and infrared spectra and byelemental analysis.

Analysis. Calcd. for C₁₉ H₁₇ O₄ Cl: C, 66.19; H, 4.97; Cl, 10.28. Found:C, 66.38; H, 5.03; Cl, 10.27.

EXAMPLE 22 ethyl 5-(4-octylphenyl)-3-oxo-4-pentenoate ##STR12##

The title compound, m.p. ca. 57°, was prepared by the method of Example1 using 4-octylbenzaldehyde instead of benzaldehyde. Structureassignment was supported by nmr and infrared spectra and by elementalanalysis.

Analysis. Calcd. for C₂₁ H₃₀ O₃ O: C, 76.33; H, 9.15. Found: C, 76.22;H, 9.37.

EXAMPLE 23 ethyl 5-(4-methoxyphenyl)-3-oxo-4-pentenoate ##STR13##

The title compound, m.p. ca. 69°, was prepared by the method of Example1 using 4-methoxybenzaldehyde instead of benzaldehyde. Structureassignment was supported by nmr and infrared spectra and by elementalanalysis.

Analysis. Calcd. for C₁₄ H₁₆ O₄ : C, 67.73; H, 6.50. Found: C, 67.67; H,6.67.

EXAMPLE 24 ethyl 5-(4-nitrophenyl)-3-oxo-4-pentenoate ##STR14##

The title compound, m.p. ca. 116°, was prepared by the method of Example1 using 4-nitrobenzaldehyde instead of benzaldehyde. Structureassignment was supported by nmr and infrared spectra and by elementalanalysis.

Analysis. Calcd. for C₁₃ H₁₃ NO₅ : C, 59.31; H, 4.98; N, 5.32. Found: C,59.32; H, 5.01; N, 5.19.

EXAMPLE 25 ethyl 5-(2-nitrophenyl)-3-oxo-4-pentenoate ##STR15##

The title compound, m.p. ca. 72°, was prepared by the method of Example1 using 2-nitrobenzaldehyde instead of benzaldehyde. Structureassignment was supported by nmr and infrared spectra and by elementalanalysis.

Analysis. Calcd. for C₁₃ H₁₃ NO₅ : C, 59.31; H, 4.98; N, 5.32. Found: C,59.45; H, 5.17; N, 5.29.

EXAMPLE 26 ethyl 5-(2-hydroxyphenyl)-3-oxo-4-pentenoate ##STR16##

The title compound was prepared as an oil by the method of Example 1using 2-hydroxybenzaldehyde instead of benzaldehyde. Structureassignment was supported by nmr and infrared spectra.

EXAMPLE 27 ethyl 5-(1-naphthyl)-3-oxo-4-pentenoate ##STR17##

The title compound was prepared as an oil by the method of Example 1using 1-naphthaldehyde instead of benzaldehyde.

Structure assignment was supported by nmr and infrared spectra and byelemental analysis.

Analysis. Calcd. for C₁₇ H₁₆ O₃ : C, 76.10; H, 6.01. Found: C, 76.22; H,6.12.

EXAMPLE 28 methyl 3-oxo-5-phenyl-4-pentenoate ##STR18##

The title compound, m.p. ca. 83°, was prepared by the method of Example1 using methyl acetoacetate instead of ethyl acetoacetate. Structureassignment was supported by nmr and infrared spectra and by elementalanalysis.

Analysis. Calcd. for C₁₂ H₁₂ O₃ : C, 70.58; H, 5.92. Found: C, 70.92; H,6.07.

EXAMPLE 29 N,N-diethyl-3-oxo-5-phenyl-4-pentenamide ##STR19##

The title compound was prepared by the method of Example 1 usingN,N-diethylacetoacetamide instead of ethyl acetoacetate. Structureassignment was supported by nmr and infrared spectra and by elementalanalysis.

Analysis. Calcd. for C₁₅ H₁₉ NO₂ : C, 73.44; H, 7.81; N, 5.71. Found: C,73.27; H, 7.86; N, 5.74

EXAMPLE 30 6-phenyl-5-hexene-2,4-dione, Procedure S ##STR20##

The title compound, m.p. ca. 82°, was prepared by the method of Example1 using 2,4-pentanedione instead of ethyl acetoacetate. Structureassignment was supported by nmr and infrared spectra and by elementalanalysis.

Analysis. Calcd. for C₁₂ H₁₂ O₂ : C, 76.57; H, 6.43. Found: C, 76.51; H,6.36.

EXAMPLE 31 6-phenyl-5-hexene-2,4-dione, Procedure T

The title compound was prepared by the method of Example 6 (that is,using 2,2,6,6-tetramethylpiperidine as base instead of triethylamine)using 2,4-pentanedione instead of ethyl acetoacetate. The materialprepared by this procedure was identical to that prepared by the methodof Example 30, as indicated by the reverse phase chromatographic methoddescribed in Example 2.

EXAMPLE 32 1,7-diphenyl-1,6-heptadiene-3,5-dione ##STR21##

Later chromatographic fractions from the preparation described inExample 30 afforded the title compound, m.p. ca. 138°. Structureassignment was supported by nmr and infrared spectra and by elementalanalysis.

Analysis. Calcd. for C₁₉ H₁₆ O₂ : C, 82.58; H, 5.84. Found: C, 82.29; H,5.78.

EXAMPLE 33 1,5-diphenyl-4-pentene-1,3-dione ##STR22##

The title compound, m.p. ca. 108°, was prepared by the method of Example1 using 1-benzoylacetone instead of ethyl acetoacetate. Structureassignment was supported by nmr and infrared spectra and by elementalanalysis.

Analysis. Calcd. for C₁₇ H₁₄ O₂ : C, 81.58; H, 5.64. Found: C, 81.42; H,5.59.

What is claimed is:
 1. A method for treating allergic reactions orinflammatory conditions in mammals comprising administering to a mammalin need of such treatment a therapeutically effective amount of acompound of the formula: ##STR23## wherein R¹ is: (a) hydrogen;(b) C₁-C₁₀ alkyl; (c) C₁ -C₆ alkoxy; (d) NR⁵ R⁶ ; wherein R⁵ and R⁶, eachbeing the same or different, are:(i) hydrogen; or (ii) C₁ -C₁₀ alkyl;(e) phenyl or phenyl substituted with 1 to 3 substituents selected fromthe group consisting of:(i) C₁ -C₁₀ alkyl; (ii) C₁ -C₆ alkoxy; (iii)nitro, with the proviso that only one such substituent may be nitro; or(iv) halogen; (f) phenoxy or phenoxy substituted with 1 to 3substituents selected from the group consisting of:(i) C₁ -C₁₀ alkyl;(ii) C₁ -C₆ alkoxy; (iii) nitro, with the proviso that only one suchsubstituent may be nitro; or (iv) halogen; (g) ##STR24## wherein R⁷, R⁸,and R⁹ each being the same or different, are:(i) hydrogen; (ii) C₁ -C₁₀alkyl; (iii) C₁ -C₆ alkoxy; (iv) benzyl; (v) phenoxy or phenoxysubstituted with 1 to 3 substituents selected from the group consistingof:(A) C₁ -C₁₀ alkyl; (B) C₁ -C₆ alkoxy; or (C) halogen; (vi) nitro,with the proviso that only one of R⁷, R⁸, and R⁹ may be nitro; (vii)halogen; (viii) hydroxyl; or (ix) R⁷ and R⁸ together are--CH═CH--CH═CH--;wherein R², R³, and R⁴, each being the same ordifferent, are: (a) hydrogen; (b) C₁ -C₁₀ alkyl; (c) C₁ -C₆ alkoxy; (d)benzyl; (e) phenoxy or phenoxy substituted with 1 to 3 substitutentsselected from the group consisting of:(i) C₁ -C₁₀ alkyl; (ii) C₁ -C₆alkoxy; or (iii) halogen; (f) nitro, with the proviso that only one ofR², R³, and R⁴ may be nitro; (g) halogen; (h) hydroxyl; or (i) R² and R³together are --CH═CH--CH═CH--.
 2. A method according to claim 1 whereinsaid compound is of the formula: ##STR25## wherein R¹ is: (a) C₁ -C₆alkoxy; or(b) phenoxy or phenoxy substituted with 1 to 3 substituentsselected from the group consisting of:(i) C₁ -C₁₀ alkyl; (ii) C₁ -C₆alkoxy; (iii) nitro, with the proviso that only one such substituent maybe nitro; or (iv) halogen;wherein R², R³, and R⁴, each being the same ordifferent, are: (a) hydrogen; (b) C₁ -C₁₀ alkyl; (c) C₁ -C₆ alkoxy; (d)benzyl; (e) phenoxy or phenoxy substituted with 1 to 3 substituentsselected from the group consisting of:(i) C₁ -C₁₀ alkyl; (ii) C₁ -C₆alkoxy; or (iii) halogen; (f) nitro, with the proviso that only one ofR², R³, and R⁴ may be nitro; (g) halogen; (h) hydroxyl; or (i) R² and R³together are --CH═CH--CH═CH--.
 3. A method according to claim 2 whereinR¹ is C₁ -C₆ alkoxy.
 4. A method according to claim 3 wherein saidcompound is of the formula: ##STR26## wherein R², R³, and R⁴, each beingthe same or different, are:(a) hydrogen; (b) C₁ -C₁₀ alkyl; (c) C₁ -C₆alkoxy; (d) benzyl; (e) phenoxy or phenoxy substituted with 1 to 3substituents selected from the group consisting of:(i) C₁ -C₁₀ alkyl;(ii) C₁ -C₆ alkoxy; or (iii) halogen; (f) nitro, with the proviso thatonly one of R², R³, and R⁴ may be nitro; (g) halogen; or (h) hydroxyl.5. A method according to claim 4 wherein said compound is selected fromthe group consisting of:ethyl 3-oxo-5-phenyl-4-pentenoate, methyl3-oxo-5-phenyl-4-pentenoate, ethyl 5-(4-octylphenyl)-3-oxo-4-pentenoate,ethyl 5-(4-methoxyphenyl)-3-oxo-4-pentenoate, ethyl3-oxo-5-(3-phenoxyphenyl)-4-pentenoate, ethyl5-[3-(4-chlorophenoxy)phenyl]-3-oxo-4-pentenoate, ethyl5-(4-nitrophenyl)-3-oxo-4-pentenoate, ethyl5-(2-nitrophenyl)-3-oxo-4-pentenoate, and ethyl5-(2-hydroxyphenyl)-3-oxo-4-pentenoate.
 6. A method according to claim 3wherein said compound is of the formula: ##STR27## wherein R² and R³together are --CH═CH--CH═CH--.
 7. A method according to claim 6 whereinsaid compound is ethyl 5-(1-naphthyl)-3-oxo-4-pentenoate.
 8. A methodaccording to claim 1 wherein said compound is of the formula: ##STR28##wherein R⁵ and R⁶, each being the same or different, are: (a) hydrogen;or(b) C₁ -C₁₀ alkyl.
 9. A method according to claim 8 wherein saidcompound is N,N-diethyl-3-oxo-5-phenyl-4-pentenamide.
 10. A methodaccording to claim 1 wherein said compound is of the formula: ##STR29##wherein R¹ is (a) hydrogen;(b) C₁ -C₁₀ alkyl; (c) phenyl or phenylsubstituted with 1 to 3 substituents selected from the group consistingof:(i) C₁ -C₁₀ alkyl; (ii) C₁ -C₆ alkoxy; (iii) nitro, with the provisothat only one such substituent may be nitro; or (iv) halogen;wherein R²,R³, and R⁴, each being the same or different, are: (a) hydrogen; (b) C₁-C₁₀ alkyl; (c) C₁ -C₆ alkoxy; (d) benzyl; (e) phenoxy or phenoxysubstituted with 1 to 3 substituents selected from the group consistingof:(i) C₁ -C₁₀ alkyl; (ii) C₁ -C₆ alkoxy; or (iii) halogen; (f) nitro,with the proviso that only one of R², R³, and R⁴ may be nitro; (g)halogen; (h) hydroxyl; or (i) R² and R³ together are --CH═CH--CH═CH--.11. A method according to claim 10 wherein R¹ is C₁ -C₁₀ alkyl.
 12. Amethod according to claim 11 wherein said compound is6-phenyl-5-hexene-2,4-dione.
 13. A method according to claim 10 whereinR¹ is phenyl or phenyl substituted with 1 to 3 substituents selectedfrom the group consisting of:(i) C₁ -C₁₀ alkyl; (ii) C₁ -C₆ alkoxy;(iii) nitro, with the proviso that only one such substituent may benitro; or (iv) halogen.
 14. A method according to claim 13 wherein saidcompound is 1,5-diphenyl-4-pentene-1,3-dione.
 15. A method according toclaim 1 wherein said compound is of the formula: ##STR30## wherein R²,R³, and R⁴, each being the same or different, are:(a) hydrogen; (b) C₁-C₁₀ alkyl; (c) C₁ -C₆ alkoxy; (d) benzyl; (e) phenoxy or phenoxysubstituted with 1 to 3 substituents selected from the group consistingof:(i) C₁ -C₁₀ alkyl; (ii) C₁ -C₆ alkoxy; or (iii) halogen; (f) nitro,with the proviso that only one of R², R³, and R⁴ may be nitro; (g)halogen; (h) hydroxyl; or (i) R² and R³ together are--CH═CH--CH═CH--.wherein R⁷, R⁸, and R⁹, each being the same ordifferent, are: (a) hydrogen; (b) C₁ -C₁₀ alkyl; (c) C₁ -C₆ alloxy; (d)benzyl; (e) phenoxy or phenoxy substituted with 1 to 3 substituentsselected from the group consisting of:(i) C₁ -C₁₀ alkyl; (ii) C₁ -C₆alkoxy; or (iii) halogen; (f) nitro, with the proviso that only one ofR⁷, R⁸, and R⁹ may be nitro; (g) halogen; (h) hydroxyl; or (i) R⁷ and R⁸together are --CH═CH--CH═CH--.
 16. A method according to claim 15wherein said compound is 1,7-diphenyl-1,6-heptadiene-3,5-dione.
 17. Amethod for treating allergic reactions in mammals comprisingadministering to a mammal in need of such treatment a therapeuticallyeffective amount of a compound according to claim
 1. 18. A method fortreating inflammatory conditions in mammals comprising administering toa mammal in need of such treatment a therapeutically effective amount ofa compound according to claim
 1. 19. A pharmaceutical compositioncomprising at least one compound of the formula: ##STR31## together withone or more non-toxic pharmaceutically acceptable carriers; wherein R¹is(a) hydrogen; (b) C₁ -C₁₀ alkyl; (c) C₁ -C₆ aIkoxy; (d) NR⁵ R⁶;wherein R⁵ and R⁶, each being the same or different, are: (i) hydrogen;or (ii) C₁ -C₁₀ alkyl; (e) phenyl or phenyl substituted with 1 to 3substituents selected from the group consisting of:(i) C₁ -C₁₀ alkyl;(ii) C₁ -C₆ alkoxy; (iii) nitro, with the proviso that only one suchsubstituent may be nitro; or (iv) halogen; (f) phenoxy or phenoxysubstituted with 1 to 3 substituents selected from the group consistingof:(i) C₁ -C₁₀ alkyl; (ii) C₁ -C₆ alkoxy; (iii) nitro, with the provisothat only one such substituent may be nitro; or (iv) halogen; (g)##STR32## wherein R⁷, R⁸, and R⁹, each being the same or different,are:(i) hydrogen; (ii) C₁ -C₁₀ alkyl; (iii) C₁ -C₆ alkoxy; (iv) benzyl;(v) phenoxy or phenoxy substituted with 1 to 3 substituents selectedfrom the group consisting of:(A) C₁ -C₁₀ alkyl; (B) C₁ -C₆ alkoxy; or(C) halogen; (vi) nitro, with the proviso that only one of R⁷, R⁸, andR⁹ may be nitro; (vii) halogen; (viii) hydroxyl; or (ix) R⁷ and R⁸together are --CH═CH--CH═CH--;wherein R², R³, and R⁴, each being thesame or different, are: (a) hydrogen; (b) C₁ -C₁₀ alkyl; (c) C₁ -C₆alkoxy; (d) benzyl; (e) phenoxy or phenoxy substituted with 1 to 3substitutents selected from the group consisting of:(i) C₁ -C₁₀ alkyl;(ii) C₁ -C₆ alkoxy; or (iii) halogen; (f) nitro, with the proviso thatonly one of R², R³, and R⁴ may be nitro; (g) halogen; (h) hydroxyl; or(i) R² and R³ together are --CH═CH--CH═CH--.
 20. A pharmaceuticalcomposition according to claim 19 wherein said compound is of theformula: ##STR33## wherein R¹ is: (a) C₁ -C₆ alkoxy; or(b) phenoxy orphenoxy substituted with 1 to 3 substituents selected from the groupconsisting of:(i) C₁ -C₁₀ alkyl; (ii) C₁ -C₆ alkoxy; (iii) nitro, withthe proviso that only one such substituent may be nitro; or (iv)halogen;wherein R², R³, and R⁴, each being the same or different, are:(a) hydrogen; (b) C₁ -C₁₀ alkyl; (c) C₁ -C₆ alkoxy; (d) benzyl; (e)phenoxy or phenoxy substituted with 1 to 3 substituents selected fromthe group consisting of:(i) C₁ -C₁₀ alkyl; (ii) C₁ -C₆ alkoxy; or (iii)halogen; (f) nitro, with the proviso that only one of R², R³, and R⁴ maybe nitro; (g) halogen; (h) hydroxyl; or (i) R² and R³ together are--CH═CH--CH═CH--.
 21. A pharmaceutical composition according to claim 20wherein R¹ is C₁ -C₆ alkoxy.
 22. A pharmaceutical composition accordingto claim 21 wherein said compound is of the formula: ##STR34## whereinR², R³, and R⁴, each being the same or different, are:(a) hydrogen; (b)C₁ -C₁₀ alkyl; (c) C₁ -C₆ alkoxy; (d) benzyl; (e) phenoxy or phenoxysubstitued with 1 to 3 substituents selected from the group consistingof:(i) C₁ -C₁₀ alkyl; (ii) C₁ -C₆ alkoxy; or (iii) halogen; (f) nitro,with the proviso that only one of R², R³, and R⁴ may be nitro; (g)halogen; or (h) hydroxyl.
 23. A pharmaceutical composition according toclaim 22 wherein said compound is selected from the group consistingof:ethyl 3-oxo-5-phenyl-4-pentenoate, methyl3-oxo-5-phenyl-4-pentenoate, ethyl 5-(4-octylphenyl)-3-oxo-4-pentenoate,ethyl 5-(4-methoxyphenyl)-3-oxo-4-pentenoate, ethyl3-oxo-5-(3-phenoxyphenyl)-4-pentenoate, ethyl5-[3-(4-chlorophenoxy)phenyl]-3-oxo-4-pentenoate, ethyl5-(4-nitrophenyl)-3-oxo-4-pentenoate, ethyl5-(2-nitrophenyl)-3-oxo-4-pentenoate, and ethyl5-(2-hydroxyphenyl)-3-oxo-4-pentenoate.
 24. A pharmaceutical compositionaccording to claim 21 wherein said compound is of the formula: ##STR35##wherein R² and R³ together are --CH═CH--CH═CH--.
 25. A pharmaceuticalcomposition according to claim 24 wherein said compound is ethyl5-(1-naphthyl)-3-oxo-4-pentenoate.
 26. A pharmaceutical compositionaccording to claim 19 wherein said compound is of the formula: ##STR36##wherein R⁵ and R⁶, each being the same or different, are: (a) hydrogen;or(b) C₁ -C₁₀ alkyl.
 27. A pharmaceutical composition according to claim26 wherein said compound is N,N-diethyl-3-oxo-5-phenyl-4-pentenamide.28. A pharmaceutical composition according to claim 19 wherein saidcompound is of the formula: ##STR37## wherein R¹ is: (a) hydrogen;(b) C₁-C₁₀ alkyl; (c) phenyl or phenyl substituted with 1 to 3 substituentsselected from the group consisting of:(i) C₁ -C₁₀ alkyl; (ii) C₁ -C₆alkoxy; (iii) nitro, with the proviso that only one such substituent maybe nitro; or (iv) halogen;wherein R², R³, and R⁴, each being the same ordifferent, are: (a) hydrogen; (b) C₁ -C₁₀ alkyl; (c) C₁ -C₆ alkoxy; (d)benzyl; (e) phenoxy or phenoxy substituted with 1 to 3 substituentsselected from the group consisting of:(i) C₁ -C₁₀ alkyl; (ii) C₁ -C₆alkoxy; or (iii) halogen; (f) nitro, with the proviso that only one ofR², R³, and R⁴ may be nitro; (g) halogen; (h) hydroxyl; or (i) R² and R³together are --CH═CH--CH═CH--.
 29. A pharmaceutical compositionaccording to claim 28 wherein R¹ is C₁ -C₁₀ alkyl.
 30. A pharmaceuticalcomposition according to claim 29 wherein said compound is6-phenyl-5-hexene-2,4-dione.
 31. A pharmaceutical composition accordingto claim 28 wherein R¹ is phenyl or phenyl substituted with 1 to 3substituents selected from the group consisting of:(i) C₁ -C₁₀ alkyl;(ii) C₁ -C₆ alkoxy; (iii) nitro, with the proviso that only one suchsubstituent may be nitro; or (iv) halogen.
 32. A pharmaceuticalcomposition according to claim 31 wherein said compound is1,5-diphenyl-4-pentene-1,3-dione.
 33. A pharmaceutical compositionaccording to claim 19 wherein said compound is of the formula: ##STR38##wherein R², R³, and R⁴, each being the same or different, are:(a)hydrogen; (b) C₁ -C₁₀ alkyl; (c) C₁ -C₆ alkoxy; (d) benzyl; (e) phenoxyor phenoxy substituted with 1 to 3 substituents selected from the groupconsisting of:(i) C₁ -C₁₀ alkyl; (ii) C₁ -C₆ alkoxy; or (iii) halogen;(f) nitro, with the proviso that only one of R², R³, and R⁴ may benitro; (g) halogen; (h) hydroxyl; or (i) R² and R³ together are--CH═CH--CH═CH--;wherein R⁷, R⁸, and R⁹, each being the same ordifferent, are: (a) hydrogen; (b) C₁ -C₁₀ alkyl; (c) C₁ -C₆ alkoxy; (d)benzyl; (e) phenoxy or phenoxy substituted with 1 to 3 substituentsselected from the group consisting of:(i) C₁ -C₁₀ alkyl; (ii) C₁ -C₆alkoxy; or (iii) halogen; (f) nitro, with the proviso that only one ofR⁷, R⁸, and R⁹ may be nitro; (g) halogen; (h) hydroxyl; or (i) R⁷ and R⁸together are --CH═CH--CH═CH--.
 34. A pharmaceutical compositionaccording to claim 33 wherein said compound is1,7-diphenyl-1,6-heptadiene-3,5-dione.
 35. A method for treatingallergic reactions or inflammatory conditions in mammals comprisingadministering a therapeutically effective amount of a pharmaceuticalcomposition of claim 19 to a mammal in need of such treatment.
 36. Amethod for treating allergic reactions in mammals comprisingadministering a therapeutically effective amount of a pharmaceuticalcomposition of claim 19 to a mammal in need of such treatment.
 37. Amethod according to claim 36 wherein said compound is selected from thegroup consisting of:ethyl 3-oxo-5-phenyl-4-pentenoate, methyl3-oxo-5-phenyl-4-pentenoate, ethyl 5-(4-octylphenyl)-3-oxo-4-pentenoate,ethyl 5-(4-methoxyphenyl)-3-oxo-4-pentenoate, ethyl3-oxo-5-(3-phenoxyphenyl)-4-pentenoate, ethyl5-[3-(4-chlorophenoxy)phenyl]-3-oxo-4-pentenoate, ethyl5-(4-nitrophenyl)-3-oxo-4-pentenoate, ethyl5-(2-nitrophenyl)-3-oxo-4-pentenoate, ethyl5-(2-hydroxyphenyl)-3-oxo-4-pentenoate, ethyl5-(1-naphthyl)-3-oxo-4-pentenoate,N,N-diethyl-3-oxo-5-phenyl-4-pentenamide, 6-phenyl-5-hexene-2,4-dione,1,5-diphenyl-4-pentene-1,3-dione, and1,7-diphenyl-1,6-heptadiene-3,5-dione.
 38. A method for treatinginflammatory conditions in mammals comprising administering atherapeutically effective amount of a pharmaceutical composition ofclaim 19 to a mammal in need of such treatment.
 39. A method accordingto claim 38 wherein said compound is selected from the group consistingof:ethyl 3-oxo-5-phenyl-4-pentenoate, methyl3-oxo-5-phenyl-4-pentenoate, ethyl 5-(4-octylphenyl)-3-oxo-4-pentenoate,ethyl 5-(4-methoxyphenyl)-3-oxo-4-pentenoate, ethyl3-oxo-5-(3-phenoxyphenyl)-4-pentenoate, ethyl5-[3-(4-chlorophenoxy)phenyl]-3-oxo-4-pentenoate, ethyl5-(4-nitrophenyl)-3-oxo-4-pentenoate, ethyl5-(2-nitrophenyl)-3-oxo-4-pentenoate, ethyl5-(2-hydroxyphenyl)-3-oxo-4-pentenoate, ethyl5-(1-naphthyl)-3-oxo-4-pentenoate,N,N-diethyl-3-oxo-5-phenyl-4-pentenamide, 6-phenyl-5-hexene-2,4-dione,1,5-diphenyl-4-pentene-1,3-dione, and1,7-diphenyl-1,6-heptadiene-3,5-dione.